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Earlier Access to Medicines – Early Access to Medicines Scheme and Adaptive Licensing pilot PSI Conference Dr Daniel O’Connor May 2014.

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Presentation on theme: "Earlier Access to Medicines – Early Access to Medicines Scheme and Adaptive Licensing pilot PSI Conference Dr Daniel O’Connor May 2014."— Presentation transcript:

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2 Earlier Access to Medicines – Early Access to Medicines Scheme and Adaptive Licensing pilot PSI Conference Dr Daniel O’Connor May 2014

3 Disclaimer The views expressed do not necessarily reflect the official position of the MHRA

4 Earlier Access to medicines –A key challenge confronting Regulators is earlier patient access to innovative medicines, particularly in areas of unmet medical need –Ultimately there is often a fine balance between ‘denying’ patients potentially useful drugs and approving products for which the drug development is considered as immature –However, it is recognised that with greater medical needs e.g. life threatening conditions with no adequate treatments, it is acceptable to make decisions based on a greater degree of uncertainty in the data ‘Evidence versus access’ balance

5 Earlier Access to Medicines –Recently two initiatives were launched to try and address some of the pressing patient access issues: A European initiative, adaptive licensing, an emerging concept of ‘staggered marketing authorisation approval’, using existing regulatory tools This more ‘systems approach’ involving more stakeholders, has also been called ‘Medicines Adaptive Pathways to Patients’ A UK initiative, Early Access to Medicines Scheme, which aims to give access to medicines that do not yet have a marketing authorisation but meet an unmet medical need

6 Early Access to Medicines Scheme

7 Ministerial Industry Strategy Group The Prime Minister’s Strategy for UK Life Sciences Early Access to Medicines Scheme Consultation Expert group on the innovation in the regulation of healthcare Early Access to Medicines Scheme consultation response Early Access to Medicines Scheme launch Step I: the Promising Innovative Medicine (PIM) Designation Step II: the EAMS Scientific Opinion EAMS Milestones

8 –The MISG brings together government and the research-based pharmaceutical industry to promote a strong and profitable UK-based pharmaceutical industry –In 2008, a proposal for an Early Access to Medicines Scheme was developed as part of a series of events established by the MISG –The Regulatory Working Group forum considered there was support from all stakeholders that earlier access to medicines could bring benefits to patients –The Working Group developed a framework for the EAMS –Acknowledging that whilst access to such medicines will – at least in most cases – be at the end of the formal development stage, the scheme could still provide potentially life-saving treatments around one year earlier than at present Ministerial Industry Strategy Group (MISG)

9 Ministerial Industry Strategy Group (MISG) The following eligibility criteria were proposed by the group: Medicines that will treat, diagnose or prevent life threatening, or seriously debilitating conditions without adequate treatment options; Data will be required that indicates that the benefit: risk profile of the medicine is positive and that it is likely to offer advantages over any existing treatment options The scheme would be limited to medicines representing a significant advance in treatment in an area of unmet need The scheme will be available for medicines that have completed Phase III trials but in exceptional circumstances an earlier authorisation may be possible (based on Phase II data) if information available merits it

10 –In December 2011 the Prime Minister announced a new Strategy for UK Life Sciences –The publication detailed actions aimed at maintaining the UK’s world-class reputation in life sciences, improving patient health and acting as a catalyst for economic growth –One of these commitments was that the MHRA will bring forward for consultation proposals for a new ‘Early Access Scheme’ –The Strategy sets out the guiding principles for the Scheme as: ‘eligible products will be determined by a scientific opinion that the likely clinical benefits outweigh the risks identified to date where there is high unmet need; NHS funding for product must be cost effective; the UK economy should benefit from the scheme’ Strategy for UK Life Sciences – EAMS Public Consultation

11 –The MHRA and Department Health launched a joint public consultation from 13 July to 5 October 2012 –The consultation introduced the scheme based on the work of the MISG – There were 26 questions in the following areas: Should a scheme be established Scope Number of products Stage of development Patient treatment if medicine fails to be granted a licence Information requirements Monitoring and surveillance Questions on funding Macroeconomic gains to the UK Fees Other questions Strategy for UK Life Sciences – EAMS Public Consultation

12 EAMS Consultation Responses –52 responses were received and the Government’s response to the consultation was published in March 2014 –Overall, there was overwhelming support for a scheme –The Government considered that the EAMS: Addresses a public health need to improve access to important innovative medicines for patients with life threatening or seriously debilitating conditions without adequate treatment options Demonstrates a commitment from the UK to pharmaceutical innovation, through the Promising Innovative Medicine designation and earlier patient uptake of new innovative medicines in the health service

13 The Expert Group on innovation in the regulation of healthcare was established in June 2012 following the Prime Minister’s Life Sciences Strategy – A group of experts drawn from government, regulators, the NHS, industry and the academic and third sector communities will meet quarterly to discuss healthcare regulation issues, including the development of new initiatives and innovations… –The group considered maximising the impact of, and learning from, the Early Access Scheme consultation –The Expert Group published a report in September 2013 –In the report, the group welcomed the proposal for a UK Early Access to Medicines Scheme and endorsed the draft Government response to the consultation –The group advised that the scheme should be launched as soon as cross- Government agreement was obtained Strategy for UK Life Sciences – UK Expert Group

14 The expert group also considered the regulatory flexibilities available in the USA and EU and noted that the two regulatory systems offered substantively similar flexibilities However, one difference was the FDA’s “breakthrough designation” that gave strong signals to investors on promising products The expert group considered that much interest has been generated by the FDA's breakthrough designation, where promising new medicinal products are designated based on preliminary clinical evidence The Expert Group recommended that the Government consider the possibility of adopting a designation that would send signals to investors (as does the US breakthrough designation), perhaps in the context of the proposed UK Early Access scheme Strategy for UK Life Sciences – UK Expert Group

15 Early Access to Medicines Launch

16 EAMS Overview –The MHRA launched the scheme on the 7 th of April with a dedicated EAMS webpage, coordinator and guidance –The scheme aims to give patients with life threatening or seriously debilitating conditions access to medicines that do not yet have a marketing authorisation when there is a clear unmet medical need –The scheme is voluntary and the opinion from MHRA does not replace the normal licensing procedures for medicines –Primarily aimed at medicines that have completed Phase III trials, but may be applied to completed Phase II trials in exceptional circumstances –There is no set limit on the numbers of products entering the scheme provided they fulfil the criteria of the scheme

17 EAMS Overview –MHRA is responsible for the scientific aspects of the scheme and the scientific opinion will be provided after a two-step evaluation process: –Step I, the Promising Innovative Medicine (PIM) designation »The designation is an early indication that a medicinal product is a promising candidate for the EAMS –Step II, the Early Access to Medicines Scientific Opinion »The scientific opinion will describe the benefits and risks of the medicine and will support the prescriber and patient to make a decision on using the medicine before its licence is approved

18 Step I PIM Designation –A Promising Innovative Medicine Designation is an early indication that a medicinal product is a promising candidate for the EAMS –A designation is a prerequisite to enter the EAMS scientific opinion assessment (step II) –The designation will be issued after an MHRA scientific meeting on the basis of non-clinical and clinical data available on the product, in a defined disease area –Applicants may apply when data from early stages of clinical development indicates that the medicinal product fulfills the designation criteria –the product is likely to demonstrate significant benefit for patients in life-threatening or seriously debilitating conditions

19 ‘PIM’ designation awarded on the basis of Phase I/II data Step IIStep I Enter Scientific review for EAMS opinion Joint ‘PIM’ designation and Early Access to Medicines pre-submission meeting, on the basis of Phase III data (exceptionally Phase II) Scientific review for EAMS opinion ‘PIM’ designation awarded on the basis of Phase II data Early Access to Medicines pre- submission meeting Enter Scientific review for EAMS opinion Enter Scientific review for EAMS opinion

20 PIM - How to apply –Applicants seeking a PIM designation should read the available guidance and complete the PIM designation template in full, indicating how the product fulfills the criteria for designation –The Application template includes: Administrative and product specific information Brief details of current pharmaceutical development Criteria 1: Details of the condition and details of the high unmet need Criteria 2: The medicinal product is likely to offer major advantage over methods currently used in the UK Criteria 3; The potential adverse effects of the medicinal product are likely to be outweighed by the benefits, allowing for the reasonable expectation of a positive benefit/risk balance –For the joint PIM designation/ pre-submission meeting, both a PIM designation application template and a pre-submission meeting template should be submitted at the time of the request

21 ‘Post PIM’ Designation Following designation, the applicant is expected to complete a clinical development programme within a reasonable time period, in order to continue with an application for an EAMS scientific opinion Designation holders will also be encourage to utilise the MHRA’s support services including: The MHRA Innovation Office that helps organisations navigate the regulatory framework Scientific advice, including: Scientific advice for specific scientific issues Broader scope meetings on less specific topics Joint scientific advice meetings with NICE, regarding clinical study design that will be used to satisfy regulatory and NICE requirements

22 Step II – Scientific Opinion –The scientific opinion will describe the benefits and risks of the medicine and will support the prescriber and patient to make a decision on using the medicine before its licence is approved –To enter step II, the Applicant must hold a PIM designation, complete the pre-submission template and attend (either in person or via teleconference) a pre-submission meeting –The aim of the pre-submission meeting is to ensure that the suitability criteria for the scheme are likely to be met and to discuss the format of the data to be submitted to support the benefit/risk opinion –After the pre-submission meeting, the MHRA will make a recommendation as to whether the product is considered a suitable candidate for step II of the EAMS –However, it is ultimately the decision of the Applicant whether to proceed with an application

23 Pre-Submission Template –The pre-submission template should include: Proposed indication and brief descriptions of the following: Summary of quality and non-clinical development programme to date Justification of eligibility for scheme –Life-threatening or seriously debilitating condition in patients with a high unmet medical need –Data available to support a positive benefit risk balance and major advantage over methods currently used in the UK Summary of proposal for on-going collection of safety and efficacy data Description of format of proposed EAMS dossier Description of on-going clinical studies and recruiting countries

24 Entry into Step II –Data format requirements are in line with established regulatory guidance (CTD) and/ or option to submit non-CTD data –The EAMS dossier should be submitted in electronic format by the date specified and agreed after the pre-submission meeting –Late or invalid dossiers will not be able to enter the scheme on the preferred date as the timetables are set to coincide with our expert committee meetings –The assessment timetable is fast and flexible, 75 (90) days vs. 150 or 210 days in the EMA centralised procedure (minus clock stops), with options: Lengthen clock stops if required Close before Day 75 if all issues are resolved

25 Days 0-45 MHRA assessment & consultation with CHM/EAG, list of outstanding issues communicated to Applicant, with provisional Benefit: Risk (B:R) opinion Preliminary positive opinion (Minor issues outstanding) Days 46-75: Final B:R decision positive on or before Day 75 Days 46-90: Final B:R decision made on or before Day 90 – positive or negative opinion MHRA considers Day 90 procedure required Days 46-75: Preliminary B:R decision now negative *in exceptional circumstances, the Applicant can request additional 30 days (30+30) Applicant requests revert to Day 90 procedure Day 75 TimetableDay 90 Timetable 15 day clock stop30 day clock stop* Preliminary negative opinion (Major issues outstanding)

26 The Scientific Opinion –The scientific opinion will describe the benefits and risks of the medicine, based on information submitted to the MHRA by the Applicant in a public assessment report (PAR) –The PAR will be made available on the MHRA’s website to assist clinicians and patients in making treatment decisions –More detailed product information will be provided in the EAMS Treatment Protocol, which will detail the conditions for use, ensuring safe and efficacious use of the product –The scientific opinion will be valid for one year, renewable if necessary and appropriate –Negative opinions will not be published

27 The Scientific Opinion PAR What is [insert product name]? What is [insert product name] used to treat/diagnoses/prevent? How is [insert product name] used? How does [insert product name] work? How has [insert product name] been studied? What are the benefits and risks of [insert product name]? –Benefits –Risks Why has [insert product name] been given a positive Early Access to Medicine Scientific opinion? What are the uncertainties? Are there on-going clinical studies? What measures are in place to monitor and manage risks?

28 Periodic Update During the opinion year, it is expected that the scientific opinion holder will provide regular updates The frequency and scope of these updates will be agreed before the issue of a positive scientific opinion but updates are likely be expected every 3 months and describe safety and usage of the product under the scheme, along with any safety and efficacy data from newly-completed clinical trials MHRA will amend the PAR and treatment protocol as necessary Where relevant, quality, safety and efficacy data generated during the EAMS opinion should be submitted at appropriate time points during the marketing authorisation application

29 EAMS Summary Open for applications since 7 th April 2014 Aim to give patients with life threatening or seriously debilitating conditions access to medicines that do not yet have a marketing authorisation when there is a clear unmet medical need The MHRA is responsible for the scientific aspects of the scheme and the scientific opinion will be provided after a two-step evaluation process Detailed guidance and templates can be found on the EAMS webpage Support through the EAMS coordinator, to provide help and assistance regarding any aspect of the scheme New scheme – New processes - MHRA plan to collection information from applicants on their experiences of the scheme (using an electronic survey)

30 Adaptive Licensing

31 Marketing Authorisation –Medicinal products for human use may only be placed on the market in the EU if a marketing authorisation has been issued by the Community or by a competent authority of a member state –For a medicine to be licensed, a marketing authorisation application must be submitted to a national competent authority or the European Medicines Agency (EMA)

32 Centralised Procedure –Regulation (EC) No 726/2004 lays down a centralised procedure for the authorisation of medicinal products: Single application and evaluation Single authorisation granted by the EC –The types of product which fall within the mandatory scope of the centralised procedure include: Medicinal products derived from biotechnology e.g. those derived from recombinant DNA technology or monoclonal antibody methods New Active Substances in the treatment of AIDS, cancer, neurodegenerative disorders, diabetes, autoimmune diseases and other immune dysfunctions and viral diseases Orphan medicinal products Optional scope e.g. products that constitute a significant therapeutic, scientific or technical innovation

33 Centralised Procedure –Administered by the European Medicines Agency (EMA) –The Committee for Medicinal Products for Human Use (CHMP) of the EMA is responsible for preparing the scientific opinion –Results in a single Community authorisation granted by the European Commission –No country withdrawals - ‘all or none’

34 Centralised Procedure –A Rapporteur and Co-Rapporteur are appointed from CHMP members –The role of the Rapporteurs is to perform the scientific evaluation and to prepare an assessment report, according to the agreed timetable –In the context of quality assurance, CHMP members may be assigned to peer review the Rapporteurs’ scientific evaluation –CHMP may consult its scientific advisory groups (e.g. SAG-O) and working parties (e.g. Biologics Working Party – BWP) –The opinion of the CHMP is given within 210 days (less clock-stops for the applicant to provide answers to questions from the CHMP)

35 Accelerated Assessment –When a MAA is submitted for a product which is of major public health interest, in particular from the viewpoint of therapeutic innovation, the applicant may request an accelerated assessment procedure –The standard timetable is reduced to 150 days –An applicant should notify the intent to submit a request for an accelerated assessment procedure –Justification for a request for accelerated assessment should include a description of: –The unmet medical needs –The extent to which the medicinal product is expected to have major impact on medical practice

36 Centralised Procedure –A marketing authorisation application may result in: –Grant (full approval) –Grant with conditions »The Commission is empowered to impose on the marketing authorisation holder the obligation to conduct post-authorisation studies on safety and on efficacy, as a condition of the marketing authorisation –Conditional approval »For certain medicines, in order to meet unmet medical needs of patients and in the interest of public health, it may be necessary to grant marketing authorisations on the basis of less complete data than is normally required –Approval under exceptional circumstances »The Applicant must demonstrate that he is unable to provide comprehensive data on the efficacy and safety under normal conditions of use

37 Summary of MA routes Centralised National MRP DCP Marketing authorisation Grant (full approval) Grant with conditions Conditional approval Exceptional circumstances Grant Grant with conditions Exceptional circumstances Accelerated assessment Fast track assessment (National only)

38 Adaptive Licensing (AL) –Adaptive licensing is proposed to be stepwise learning under conditions of acknowledged uncertainty, with iterative phases of data gathering and regulatory evaluation - a life-cycle approach –This is in contrast to traditional drug licensing approaches that are based on binary decisions, where an experimental therapy is transformed into a ‘fully’ vetted therapy at the moment of licensing –The aim is to maximise the positive impact of new drugs on public health by: Balancing timely access for patients to treatments that promise to address serious conditions where there is an unmet need With the need to provide adequate evolving information on the benefits and harms

39 Adaptive Licensing (AL) –AL is defined by the EMA as a prospectively planned, adaptive approach to bringing drugs to market; Starting from an authorised indication, most likely a “niche” indication Followed by iterative phases of evidence gathering and progressive licensing adaptations, concerning both the authorised indication and further therapeutic uses of the drug –AL uses the regulatory processes that exist with the EU framework –Stakeholders other than regulators and industry need to be involved in planning and agreeing the manner in which clinical trial and post-authorisation data will be generated for decision making: e.g. Reimbursement authorities, patient organisations, societies involved in treatment guidelines

40 The EMA pilot –An AL discussion group was set up by the EMA in 2012, with members from across the various scientific committees e.g. CHMP, COMP –Following work performed by the group, the EMA recently launched an adaptive licensing pilot (March 2014) to discuss prospective case studies –The purpose of the pilot is to provide a framework for informal interactions by discussing ‘live assets’, i.e. medicines currently under development –It is hoped that all stakeholders will be able to address a range of technical and scientific questions Help refine how future AL pathways might be designed What might be achieved by AL How best to address the potential blocking factors To identify additional hurdles or issues that may not have become apparent yet

41 The EMA pilot –Guidance and a framework to guide discussions of individual pilot studies has been published, alongside some retrospective case studies –Discussions on possible AL pathways of a live asset are of an exploratory nature –Thus the pilot offers a safe-harbour environment for informal, non-binding discussions between regulators and companies with an ‘asset’ that may be suitable for this approach –Strengths and weaknesses of all options for development, licensing and assessment may be explored openly and discussed without fear or favour in advance of more formal interactions e.g. scientific advice –Companies who are interested in participating are invited to submit medicines for consideration as prospective pilot cases Live assets shall be experimental drugs or biologicals in the early stage of clinical development to enable actionable input from stakeholders (prior to initiation of confirmatory studies)

42 The EMA pilot –Companies should complete a high-level framework on which to base the pilot study –Product name/identifier –Summary of relevant product data and development to date (Licensing history and interactions with health authorities/payers/HTA bodies) –Proposal for development under adaptive licensing ‘adaptive’ strategies for development, licensing, patient access, appropriate utilization, and monitoring that could be considered, using existing regulatory tools –Outline a vision and timeline for how regulatory, payer and other stakeholders’ interactions might look, including indicative timelines for regulatory evaluation and decision making through the product lifecycle

43 AL Summary –AL would not result in a new type of Marketing Authorisation as the process would uses existing regulatory tools e.g. ‘Conditional’ MA –The novel aspects of an adaptive licensing from the perspective of the regulator relate to increased dialogue with other stakeholders and increased collection and utilisation of post-authorisation data –Possible benefits of AL could include: Maximize the positive impact of new drugs on public health by balancing timely access for patients with the need to provide adequate evolving information on benefits and harm  More rapid access to patients in greatest need Streamlined drug development with efficient generation of evidence to satisfy the needs of multiple stakeholders using parallel ‘Scientific Advice’ Potential for more rapid return on investment Earlier dialogue promoting more certainty for the drug developer

44 Thank You

45 © Crown copyright 2013 About copyright All material created by the Medicines and Healthcare Products Regulatory Agency, including materials featured within these Medicines and Healthcare Products Regulatory Agency presentation notes and delegate pack, is subject to Crown copyright protection. We control the copyright to our work (which includes all information, database rights, logos and visual images), under a delegation of authority from the Controller of Her Majesty’s Stationery Office (HMSO). The Medicines and Healthcare Products Regulatory Agency authorises you to make one free copy, by downloading to printer or to electronic, magnetic or optical storage media, of these presentations for the purposes of private research, study and reference. Any other copy or use of Crown copyright materials featured on this site, in any form or medium is subject to the prior approval of the Medicines and Healthcare Products Regulatory Agency. Further information, including an application form for requests to reproduce our material can be found at Material from other organisations The permission to reproduce Crown copyright protected material does not extend to any material in this pack which is subject to a separate licence or is the copyright of a third party. Authorisation to reproduce such material must be obtained from the copyright holders concerned.

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47 Qualification of novel methodologies David Brown, May 2014

48 Qualification opinions Published Comments Stored at this memorable URL: es/regulation/document_listing/document_listing_ jsp&

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50 Problem statement Failure rate of Phase III trial reaches to 50%, part of the failure is attribute to improper target dose estimation and selection in Phase II, and incorrect/incomplete dose-response knowledge; A number of high-profile withdrawals from market of approved drugs; FDA reported 20% of the approved drugs between 1980 and 1989 had the initial dose changed by more than 33%, in most cases lowering it.

51 Current approaches Differ by therapeutic area, but… Narrow dose range (3-4 fold max?) Few doses (2-3 max) Analysed through pairwise comparisons to placebo, e.g. ANOVA –Inefficient –Wrong question? –Multiple tests

52 Other background EMA/EFPIA workshop on M&S, Re: dose-finding: –Some surprise that we are interested –Work done that we don’t see Regulatory attitude to exploratory development -‘therapeutic efficacy’ and ‘benefit-risk’ - in the end if ‘benefit-risk’ is positive we will (must) licence it regardless of dose -‘dose-selection is the sponsors risk’

53 Other background EMA/EFPIA workshop on M&S, Re: dose-finding: –Some surprise that we are interested –Work done that we don’t see Regulatory attitude to exploratory development -‘therapeutic efficacy’ and ‘benefit-risk’ - in the end if ‘benefit-risk’ is positive we will (must) licence it regardless of dose -‘dose-selection is the sponsors risk’ -selecting dose on a weak basis is a risk for development

54 Sound science (1) “What is most helpful in choosing the starting dose of a drug is knowing the shape and location of the population (group) average dose-response curve for both desirable and undesirable effects.” “Assessment of dose-response should be an integral component of drug development with studies designed to assess dose-response an inherent part of establishing the safety and effectiveness of the drug. If development of dose-response information is built into the development process it can usually be accomplished with no loss of time and minimal extra effort compared to development plans that ignore dose-response.”

55 Sound science (2) “Conducting dose-response studies at an early stage of clinical development may reduce the number of failed phase 3 trials, speeding the drug development process and conserving development resources.” “in light of the studies that partly defined the proper dose range, further dose-finding might be pursued in the post-marketing period”

56 Sound science (3) “It is important to choose as wide a range of doses as is compatible with practicality and patient safety to discern clinically meaningful differences.” “It is all too common to discover, at the end of a parallel dose-response study, that all doses were too high (on the plateau of the dose-response curve), or that doses did not go high enough. A formally planned interim analysis (or other multi- stage design) might detect such a problem and allow study of the proper dose range.”

57 Sound science (4) “Several dose levels are needed, at least two in addition to placebo, but in general, study of more than the minimum number of doses is desirable. A single dose level of drug versus placebo allows a test of the null hypothesis of no difference between drug and placebo, but cannot define the dose-response relationship. Similarly, although a linear relationship can be derived from the response to two active doses (without placebo), this approximation is usually not sufficiently informative. Study designs usually should emphasize elucidation of the dose-response function, not individual pairwise comparisons.

58 Sound science (5) “Agencies should also be open to the use of various statistical and pharmacometric techniques such as Bayesian and population methods, modeling, and pharmacokinetic-pharmacodynamic approaches.” From which document are these quotes?

59 Sound science (6) ICH E4 - DOSE-RESPONSE INFORMATION TO SUPPORT DRUG REGISTRATION 1994 !! Not novel in principle

60 Difference to traditional ANOVA approach –Use of dose-response modelling –But, taking model uncertainty into account at design and analysis stage Background on MCP-Mod methodology  MCP-Mod stands for: Multiple Comparisons & Modelling Combines testing and estimation  Design stage Pre-specification of candidate dose- response models  Analysis stage: MCP-step Statistical test for dose-response signal. Model-selection based on significant dose-response models  Analysis stage: Mod-step Dose-response and target dose estimation based on dose-response modelling 60| SAWP Discussion Meeting | Novartis | 10 July 2013 | MCP-Mod Qualification Opinion | Business Use Only

61 As one of the two major classical strategies in dose finding trials: multiple comparison procedures and model-based approaches. –Assumes a functional relationship between the response and the dose (a quantitative factor) according to a pre- specified parametric model, e.g. logistic, an Emax or a linear log-dose model; –The fitted model is then used to estimate an adequate dose to achieve a desired response. –However, validity of trial conclusions highly depends on the correct choice of the dose-response model, which is an unknown priori. Choice of a working model may have a substantial impact on dose selection, and model selection using observed data needs to account for statistical uncertainty and associated multiplicity issues. Basic idea - modelling

62 MCP-mod - Description The MCP-Mod approach impacts both the design and the analysis of dose finding studies At the trial design stage, a suitable set of candidate models is identified in repeated clinical team discussions, which also impacts decisions on the number of doses, required sample sizes, patient allocations, etc. At the trial analysis stage, dose response is tested using suitable trend tests deduced from the set of candidate models. Once a dose response signal is established, the best model(s) out of the set of pre- specified candidate models is (are) then used for dose response and estimation of target dose or dose range.

63 MCP-mod - Description Step 1: Set of candidate models Step 2: Optimal model contrasts Step 3: Testing for dose response signal Step 4: Model selection Step 5: Dose estimation

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65 Power to detect dose response under active DR profiles.

66 Probabilities of identifying clinical relevant dose under flat dose response.

67 MCP-mod - Validation It is concluded that MCP-Mod controls type I error rate and is less likely (than ANOVA) to identify a clinically relevant dose in the absence of dose-response (flat profile). It is further concluded that under active dose-response profiles the probability of identifying dose-response will be higher, though the probability of identifying a clinically relevant dose will depend on the shape of the dose-response curve. For the simulations investigated MCP-Mod appears to be better, at least on average, than an ANOVA based approach in terms of bias and absolute error. It is widely known of course that biased estimates will, on average, result when selecting a dose based on a particularly impressive pairwise comparison to control because of random highs and this phenomenon is displayed in the simulations, but controlled by MCP-Mod.

68 Example Chronic Obstructive Pulmonary Disease (COPD). The investigational drug NVA237 is a dry powder formulation of the muscarinic receptor antagonist glycopyrronium bromide being developed by Novartis The primary purpose of the A2205 study was to provide data about the risk-benefit of four doses of NVA237 (12.5, 25, 50 and 100μg o.d.) and open- label tiotropium (18μg) so that an optimal dose of NVA237 can be chosen for Phase III studies FEV1

69 Step 1: Set of candidate models

70 Example Step 2: Optimal model contrasts Step 3: Testing for dose response signal –Applying the optimal contrasts to the treatment estimates, one obtains that all contrasts had test statistics > 6 and multiplicity adjusted p-values < As a result, the significance of the dose response signal was established and all models were considered in the next step.

71 Example Step 4: Model selection The AIC criterion was used to select the best model. Note that, even though there are two Emax shapes in the candidate set, only one Emax fit is obtained. Based on the AIC results, the Emax model was chosen to represent the dose response profile.

72 Example Step 5: Dose estimation Based on the fitted Emax of Step 4, the smallest dose giving the clinically relevant improvement over placebo of 0.12 L is estimated to be 44 μg. This is the MED estimate produced by MCP-Mod in this study. The precision of the MED estimate was evaluated via a bootstrap approach: The 90% confidence interval for the MED, corresponding to the 5% and 95% quantiles of the bootstrap sample, was [18, 81], reflecting the uncertainty in the estimate. Figure 3-6 displays the fitted model and corresponding confidence intervals. A side note on interpolation

73 MCP-mod - Conclusions … a strategy based on a modelling approach that attempts to quantify a dose-response relationship may offer an improved basis for decision making and it is arguable therefore that to qualify MCP-Mod as an improvement over the commonly used approach is uncontroversial … much of the theory underpinning the proposed method is not novel, yet the use of this type of approach in regulatory submissions remains rare and hence, the fact that these sub-optimal approaches persist makes this a relevant topic for a CHMP opinion. … more broadly, it is considered that the planning needed to implement MCP-Mod will be beneficial for trial design both in terms of the number of doses and the increase in the range of doses studied, and also in that the consequences and risks of selecting a particular trial objective, design and sample size will be better understood by all stakeholders.

74 MCP-mod - Conclusions Another interesting part of the procedure relates to the control for multiple comparisons. Designing an experiment that permits conclusions to be drawn with control of false-positive error rate is clearly desirable for the study sponsor. It is mandated by regulators in the confirmatory phase of development, though not in the exploratory phase that is under discussion here, where factors other than strict type I error control may influence decisions regarding future clinical development. The choice of 5% used by the applicant in their illustrations is arbitrary and could be varied based on the certainty that the applicant wish to have for their decision-making.

75 MCP-mod - Conclusions It is concluded that the MCP-Mod approach can be qualified as an efficient statistical methodology for model-based design and analysis of phase II dose finding studies under model uncertainty MCP-Mod represents one tool in the toolbox of the well-informed drug developer. In that sense, this opinion does not preclude any other statistical methodology for model-based design and analysis of exploratory dose finding studies from being used.

76 MCP-mod - Public consultation Lots of modelling approaches are possible –Most modelling is (almost by definition) without control for multiple testing –Don’t only focus on dose Agree, providing this is not the only permitted approach A side note on adaptive allocation

77 MCP-mod - Public consultation The current work covers a very important topic. Phase II dose response studies should be designed and analysed around dose response modelling. It is woeful that in 2013 we are discussing whether dose response modelling should be employed for dose response studies. Of course they must be. Are there idiots out there who would disagree?! The "current practice" of multiple pairwise comparisons to placebo is truly terrible. The document comments that "...that current practice is repeatedly sub-optimal and inefficient." This sentence is "too polite". To design studies to determine the dose response without consideration of dose response modelling is wholly unscientific and unethical. For an overview on how I see drug development, you might wish to view:

78 What does it mean for us? Not sure yet Potentially, more complex, but larger and more informative exploratory trials EMA workshop on dose-finding, Dec 2014

79 Conclusions MCP-Mod approach is qualified as an efficient statistical methodology for model-based design and analysis of phase II dose finding studies under model uncertainty = we have seen it, thought about it and, within the context of use, endorse it (in principle). Qualification speaks to MCP-mod but should also stimulate awareness that regulators value dose- finding and exploratory development

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81 The CAMD Consortium Nonmember participants: Academic key opinion leaders, CROs 81

82 Broad and Complete Data Sources Used for Model Development Data to inform natural history of AD Data from multiple sponsors to inform control arm elements -Placebo response -Drop-out -Covariate effects Tool is unique in that it also utilizes Literature meta data to inform drug responses -Marketed Symptomatic Agents o Magnitude, onset of effect, offset 82

83 The idea is to model the data from the placebo arms of clinical trials in Alzheimer’s disease Use the model to help the planning of future trials Perform clinical trial simulations Optimise the design in terms of aspects such as time-points to measure at, study duration, important covariates, sample size, crossover/parallel group etc

84 Context of use

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86 Baseline severity MMSE 27+/30 is normal

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88 Age

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90 Gender and ApoE4 genotype

91 Dropout

92 Modelling

93 Independent validation

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95

96

97

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99 Qualification

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102 Conclusion In a way risk free for CHMP Not going to replace clinical trials But can help their design So happy to endorse based upon our assessment

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